This invention relates to compounds of rifamycin derivatives having antimicrobial activities, their compositions, and methods for treatment and prevention of microbial infections. More particularly, the rifamycin derivative of the current invention is a rifamycin moiety covalently linked to a linker through an iminomethylenyl group (—CH═N—) at the C-3 carbon of the rifamycin moiety and the linker is, in turn, covalently linked to a quinolone moiety. The rifamycin derivatives are active against drug-resistant microorganisms with reduced frequency of developing mutational resistance in the microorganisms.
Rifamycins are natural products with potent antimicrobial activity. Examples of the naturally-occurring rifamycins are rifamycin B, rifamycin O, rifamycin R, rifamycin U, rifamycin S, rifamycin SV and rifamycin Y (Brufani, M., Cerrini, S., Fedeli, W., Vaciago, A. J. Mol. Biol. 1974, 87, 409-435). The therapeutic applications of the naturally-occurring rifamycins are limited due to their poor pharmacokinetics and oral bioavailability, weak activity against Gram-negative pathogens and low distribution into the infected tissues. Significant efforts have been made toward identifying semi-synthetic rifamycin derivatives to address the deficiencies. As a result, many semi-synthetic rifamycin derivatives with improved spectrum and pharmacological profiles have been identified. Among the semi-synthetic compounds, rifampin, rifabutin and rifapetine have been developed into therapeutic agents and are currently used for the treatment of tuberculosis and other microbial infections (Farr, B. M. Rifamycins, in Principles and Practice of Infectious Diseases; Mandell, G. L., Bennett, J. E., Dolin, R., Eds.; Churchhill Livingstone: Philadelphia; p348-361).
At present, one of the major problems associated with the rifamycin class of antimicrobial agents, like rifampin, is their rapid development of microbial resistance. Mutations in the target RNA polymerase are mainly responsible for the high frequency of microbial resistance to rifamycins. Consequently, rifamycins are currently used only in combination therapies with other antibiotics to minimize the development of resistance to this class of drugs. Rifamycin compounds of the current invention are designed to address both the rifamycin and quinolone resistance problems by attaching a quinolone core or quinolone antibiotic pharmacophore to the C-3 position of the rifamycin core structure. The resulting rifamycin compounds exert their antimicrobial activity through multiple antibacterial mechanisms targeting bacterial RNA polymerase, DNA gyrase and DNA topoisomerase IV and therefore exhibit reduced frequency of resistance.
Reference is made to U.S. Pat. No. 5,786,350 that discloses a series of C-36 derivatives of rifamycin, including derivatives formed by linking the C-3 carboxy group of a quinolone to the C-36 position of a rifamycin molecule through a chemically or metabolically labile ester group. The compounds of the current invention are structurally distinct from the previously disclosed compounds in several ways: 1) the linking point of rifamycin is the C-3 position rather than the C-36 position; 2) the linking point of the quinolone core is the C-7 position of the quinolone rather than the C-3 position carboxylic acid; and 3) the linker group contains a stable hydrazone linkage in the current inventive rifamycins rather than a metabolically unstable ester in the referenced compounds.
Reference is also made to PCT application WO 03/045319 A2 that discloses rifamycin derivatives formed by linking rifamycin and a therapeutic drug and the use of these rifamycin derivatives as vehicles for delivering the therapeutic drug. The current non-pro-drug invention differs from the referenced pro-drug strategy. In addition, this reference failed to demonstrate by specific examples that any drug is introduced to the C-3 position of a rifamycin molecule. The reference also failed to demonstrate by example that a quinolone antibiotic or its pharmacophore structure is linked to any position of rifamycin molecule.